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An Acrodermatitis Enteropathica-Associated Zn Transporter, ZIP4, Regulates Human Epidermal Homeostasis.
- Source :
-
The Journal of investigative dermatology [J Invest Dermatol] 2017 Apr; Vol. 137 (4), pp. 874-883. Date of Electronic Publication: 2016 Dec 07. - Publication Year :
- 2017
-
Abstract
- Acrodermatitis enteropathica is an autosomal recessive disorder characterized by scaly eczematous dermatosis accompanied by alopecia and diarrhea. Various mutations in the SLC39A4 gene (ZIP4), which encodes a zinc transporter, are responsible for this disorder. However, the molecular mechanism underlying the involvement of ZIP4 in the pathogenesis of this condition has yet to be established. In this study, we report the role of ZIP4 in human epidermis. ZIP4 is predominantly expressed in human keratinocytes, and its expression is dramatically reduced on epidermal differentiation. ZIP4 knockdown in human keratinocytes down-regulates zinc (Zn) levels and the transcriptional activity of a key epidermal Zn-binding protein, ΔNp63, and dysregulates epidermal differentiation in a reconstituted human skin model, resulting in the appearance of proliferating keratinocytes even in the uppermost layers of the skin. We verified that, among the amino acid residues in its Zn-binding motif, Cys205 is critical for the processing and nuclear distribution of ΔNp63 and, therefore, Zn-dependent transcriptional activity. Our results suggest that ZIP4 is essential for maintaining human epidermal homeostasis through the regulation of Zn-dependent ΔNp63 activity and can provide insight into the molecular mechanisms responsible for the cutaneous symptoms observed in Acrodermatitis enteropathica patients.<br /> (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Acrodermatitis metabolism
Adult
Aged
Blotting, Western
Carrier Proteins genetics
Cells, Cultured
Epidermis metabolism
Female
Homeostasis genetics
Humans
Keratinocytes cytology
Keratinocytes metabolism
Male
Middle Aged
Real-Time Polymerase Chain Reaction
Reference Values
Sampling Studies
Young Adult
Zinc metabolism
Acrodermatitis genetics
Cation Transport Proteins genetics
Cell Differentiation genetics
Gene Expression Regulation genetics
RNA, Small Interfering metabolism
Zinc deficiency
Subjects
Details
- Language :
- English
- ISSN :
- 1523-1747
- Volume :
- 137
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- The Journal of investigative dermatology
- Publication Type :
- Academic Journal
- Accession number :
- 27940220
- Full Text :
- https://doi.org/10.1016/j.jid.2016.11.028